Wednesday, May 17, 2017

Consult Rounds: Topiramate and the Kidney

Topiramate was first introduced to treat seizures but now is increasingly used to treat migraines and is among the top 6 drugs sold in the United States. In addition, it is used as a weight loss agent as well. Renal toxicity with this agent is not uncommon.

The three forms of renal toxicity are:

Kidney Stones
Renal Tubular Acidosis
Isolated hypokalemia

A study in 2006 published in AJKD showed that topiramate acts through multiple mechanisms, 1 of which is the inhibition of carbonic anhydrase, as in vitro studies have shown. Several case reports described a link between topiramate and the formation of calcium phosphate stones, but the mechanism for this is largely unknown.

The authors conclude that taking topiramate for about 1 year caused systemic metabolic acidosis, significantly increased urine pH, and markedly lowered urine citrate — changes that increase the propensity to form calcium phosphate stones.

With the increasing use of topiramate, reports have emerged that topiramate can cause metabolic acidosis in some patients. It does this by impairing both the normal reabsorption of filtered HCO(3)(-) by the proximal renal tubule and the excretion of H(+) by the distal renal tubule. This combination of defects is termed mixed proximal and distal RTA. Topiramate-induced RTA can make patients prone to kidney stones as stated earlier as well.  The utility of regular monitoring of HCO(3)(-) levels has not been proven and is not routine practice currently.

Finally, isolated refractory renal wasting of potassium has also been reported with this agent.

A large systematic review confirmed the above findings of renal toxicity with this agent. Fourty-seven reports published between 1996 and 2013 were retained for the final analysis. Five case-control studies and six longitudinal studies addressed the effect of topiramate on acid-base and potassium balance. A significant tendency towards mild-to-moderate hyperchloraemic metabolic acidosis (with bicarbonate ≤21.0 mmol l(-1) in approximately every third case) and mild hypokalaemia (with potassium ≤3.5 mmol l(-1) in 10% of the cases) was noted on treatment with topiramate, which was similar in children and adults.

Finally,increasing evidence supports the use of topiramate. Topiramate is generally well tolerated, and serious adverse events are rare. Nonetheless, it is linked with the development of acidosis, hypokalaemia, hyperuricaemia and hypocitraturia and eventually renal stones.

Monday, May 15, 2017

Master teacher: how do you define one?

Image result for master teacher

What makes a “master clinician teacher”—adapted from George Couros, an educator.

This list can be used for teachers in med students, residency and in nephrology fellowship as well.

·         Connects with students and gets to know them individually.
·         Helps students to meet their own individual needs as each might have their own learning styles
·         Makes the curriculum and what is taught relevant.
·         Works with students to develop their love of learning, helping students to find their own spark in learning( concept of intrinsic motivation –often lacking in our trainees)
·         Keeps themselves as a teacher up-to-date. Education and learning will always change ( being a learner for life makes you a better teacher)
·         Focuses on learning goals as opposed to performance goals.
·         Ensures that “character education” is an essential part of learning. Students need to grow emotionally as well as mentally( this is critical in creating the culture for constant life long learning and work life balance)
·         Is passionate about the content they teach( THIS is by far the MOST important quality)
·         Is concerned not just with what is taught in their class but with their overall impact on the school culture( Making a cultural difference is critical on perhaps methods of teaching)
·         Communicates well with all the stakeholders and not just the students( a subtle but needed politician)

·         Behaves as a facilitator of learning- not a “spoon feeder”

All our fellows out there, I am sure you have one mentor who exemplifies these qualities. This is what makes the experience of learning a more meaningful experience. Please take a minute to salute and respect all our teachers and educators in our lives. They teach you medicine but they also may be teaching you a way of life!

Tuesday, May 9, 2017

In the NEWS: Too much salt intake doesn't lead to increased water drinking

Two published studies in JCI might change how we think the body handles “too much salt”

What we learnt in medical school:

If you eat a lot of salt — sodium chloride — you will become thirsty and drink water, diluting your blood enough to maintain the proper concentration of sodium. Ultimately you will excrete much of the excess salt and water in urine.

When salt intake was increased in Russian cosmonauts studied, the urine Na excretion did increase as expected. But, the urine volume was not associated with those changes. When salt intake was high, the folks drank less water in the long run and still excreted increased water amounts. Where was this extra water coming from? The crew members were increasing production of glucocorticoid hormones, which influence both metabolism and immune function and allowed fat breakdown leading to water production.

Taking these observations to the lab, the investigators began a study of mice in the laboratory. The more salt the investigators added to the animals’ diet, the less water the mice drank(counter to what we think science teaches us when we eat a high salt diet). The animals were getting water by not drinking it but via  increased levels of glucocorticoid hormones breaking  down fat and muscle in their own bodies. This freed up water for the body to use.
Now published, the authors report the unexpected observation that long-term high salt intake did not increase water consumption in humans but instead increased water retention. Moreover, salt and water balance was influenced by glucocorticoid and mineralocorticoid fluctuations. 
This leads to a even bigger question? – does high salt intake= potential weight loss as fat breakdown is happening? So in other words, a high salt intake body is behaving similar to a starving body.

 I am sure that there is more to it!  In the long run, this is probably not a good adaption of the body and high glucocorticoid state is likely a risk of diabetes.  But these studies show us that we really don’t understand salt homeostasis in humans as we thought we did.

Bravo to the scientists on publishing this alternate view on salt intake and water production.

Monday, May 1, 2017

In the NEWS: AKI and marathon runners

An interesting study in AJKD published revealed a possible risk of AKI with marathon runners. This is the first study to evaluate urine microscopy in parallel with conventional and novel biomarkers of injury and repair in marathon runners. The authors prospectively showed that the AKI in runners is secondary to structural injury, mainly acute tubular injury, as evidenced by serum creatinine levels, urine microscopy analysis, and levels of novel biomarkers of injury and repair.

One would expect these changes likely were related to elevated CPK levels and rhabdomyolysis.  Interesting, while the subjects had high CPK levels, they did not correlate with AKI episodes. The authors hypothesize that heat stress and increase in core body temperature along with systemic inflammation are likely associated with AKI in marathon runners. They said that this might be similar to the CKD that is prevalent in Central American in sugarcane workers. Agricultural workers have been shown to have acute decreases in kidney function and progression to CKD associated with dehydration, systemic inflammation, and oxidative stress.  It is also possible that compared with agricultural workers, marathon runners have controlled ischemic preconditioning throughout their training, which may improve the kidney’s ability to better tolerate repeated injury.  That is an interesting analogy.

82% developed AKIN defined stage 1 and 2 AKI. A total of 16 (73%) runners were scored as having positive microscopy findings on day 1 or day 2. Some ( minor amount ) were taking NSAIDS but 50% were on some form of herbal medications.  Regardless, this is an interesting study and perhaps should be repeated in a larger marathon population such as the NYC marathon. In addition, curious what the hyponatremia incidence was? 

Monday, April 10, 2017

Topic Discussion: Capillary Leak Syndrome

A recent review in KI summarizes the pathophysiology of capillary leak syndrome and numerous etiologies that can cause it along with an interesting management strategy.

Besides sepsis, capillary leak syndrome(CLS) can be seen in:

1.       Drug induced CLS—classically interleukin 2, gemcitabine and certain monoclonal antibodies such as OKT3, anti CD-28 antibody TGN1412  ( steroids can help treat)
2.       Engraftment syndrome- seen post HSCT ( usually 4-7 days post) with increased inflammatory markers and AKI( 12-25% in most HSCT patients)( steroids can help treat)
3.       Differentiation syndrome( retinoic acid) – steroids help in this situation as well
4.       Ovarian hyperstimulation syndrome(OHSS)—two variants( early time course, vs late following HCG treatment)—supportive care
5.       Hemophagocytic lymphohistiocytosis
6.       Hemorrhagic fever( viruses such as Ebola, Marburg, Puumala)
7.       Clarkson’s disease( idiopathic CLS)—supportive therapy, IVIG, theophylline
8.       Others:- snake bites, Ricin overdose, APLAS, Kawasaki disease

In addition to hypotension, cytokines are likely to be important in the pathophysiology of acute kidney injury in capillary leak syndrome. Fluid management is a critical part of the treatment of capillary leak syndrome; hypovolemia and hypotension can cause organ injury, whereas capillary leakage of administered fluid can worsen organ edema leading to progressive organ injury.
The first phase of treatment is volume resuscitation including fluids, pressors and or IV albumin. The second phase includes loop diuretics, diuretics with albumin and finally renal replacement therapy.

Full article here

Sunday, April 9, 2017

Case 90: Answers and Summary

Which of the following is a risk factor for bleeding post kidney biopsy?

This is a tough question. Traditionally, many have thought that ASA is a known risk factor for bleeding post kidney biopsy. A recent large study states otherwise. In a large observational study published in CKJ, >2000 patients were reviewed. The incidence of major bleeding was 2.2%.  The risk factors as assessed by statistics were need for emergent biopsy as oppose to elective renal biopsy. No major risk was noted with ASA use and BMI.  There is data from prior studies suggesting no major risk with amyloidosis unless there is a factor XII deficiency associated with the amyloidosis. Emergent need for a kidney biopsy seems to be the major risk factor more than the others. 

Tuesday, March 21, 2017

Consult Rounds: Pathology of Pre-eclampsia

Image source: JASN 2007

What do you find in the kidney biopsy of a patient with pre-eclampsia?
The immunofluorescence findings are somewhat variable with fibrin deposition often being a prominent feature.

The renal biopsy findings of preeclampsia closest to look in the context of the pathologic patterns seen in thrombotic microangiopathies (TMA). The lesions of preeclampsia share some similarities with and also some differences from those of non-preeclamptic TMA, likely owing to their differing pathogenesis.

What is the LM finding?

The glomeruli are enlarged and solidified (“bloodless”), as a result of narrowed or occluded capillary lumens that are the result of swelling of the native endothelial cells and, to a lesser extent, mesangial cells. The endothelial changes are limited to the glomerular capillaries; arterioles are typically unaffected. Thrombosis by light microscopy is decidedly unusual. In marked contrast, in nonpreeclamptic TMA, thrombosis of vessels and/or glomeruli is a central finding. Cases of severe preeclampsia with accompanying vascular thrombosis often have clinical signs suggesting a superimposed nonpreeclamptic TMA. In severe cases of preeclampsia, in particular as the lesions evolve/resolve, mesangial interposition can be seen, a finding shared with other entities resulting from chronic endothelial insult, such as “chronic” TMA or transplant glomerulopathy. So essentially, it may appear on LM in some cases- as an MPGN pattern of injury ( without the IF being positive for complements or immunoglobuins). This form of injury is termed “Glomerular endotheliosis” 

What is the EM finding?

Ultrastructural analysis will show endothelial cells with loss of fenestrations with cytoplasmic swelling, owing to fluid and lipid accumulation and capillary occlusion.

What is the IF finding?

How is it different from your “classic” non preeclamptic TMA that you might see with SLE or APLAS or in TTP?

The main finding in the “classic” TMA is thrombosis of vessels and glomeruli as the main finding with some endotheliosis. This is a rare finding in pre-eclampsia related TMA unless it is very severe.

Here is a link to a nice review:

Saturday, March 11, 2017

#Visual Abstracts: History and Future in Medicine and Nephrology

Visual abstracts have flooded the social media world in the last few months. Where did this come from and how does it impact nephrology sharing of knowledge?

Looking back I found that these existed for many years in Chemistry journals –also called graphical abstracts.  Visual or graphical abstracts are visual elements that are clearly and in short figure formed conveying the main message of the research( or review) paper.  They are self explanatory and together with the title of the paper convey the main message of the article. Given the current attention spans of readers being short and many learners being “visual”, this method can be quite effective. Journals in medicine are trying to play with this concept for their specific fields.

Dr. Andrew Ibrahim( , creative director of Annals of Surgery began this revolution in Medicine. As per a twitter chat, he mentioned “ We pitched this idea to the editors of Annals of Surgery and they loved it. It was clear in June 2016 that it disseminated faster. This led to a case control cross over of 44 articles between July and Dec 2016 and results are preliminary results are promising.  The articles got read three times more if they had a visual abstract!! Once in Dec 2016, I shared my primer, there are around 20 other journals doing this.”

In the world of Nephrology, Joel Topf took on this venture for and visual abstracts appeared for the first time in renal world at recent journals club in Fall of 2016.

Following that, the #nephmadness 2017 has featured many visual abstracts, some pasted below

To top it all, CJASN is the first renal journal to enter in the visual abstract world. Great start and totally amazing to have a renal journal embrace this!

Here is an image showing early leaders of visual abstracts ( courtesy Andrew)

Few that I have done

How to create them? Check  out this primer by Andrew
You can create both static and animated abstracts- both can be very important in relaying your message.  I would urge all educators to try this out.

This could make fellowship journal club more fascinating. Make your residents/fellows create them. All researchers should simplify their ideas using such techniques.  All medicine journals should strongly consider this modality.

A new wave of presenting research has arrived- #visual abstracts!

Thursday, March 9, 2017

Concept Map: HSCT related renal disease: big picture

Here is a big picture overview of AKI and CKD seen with bone marrow transplant patients
Click on image for bigger picture.

AMACING trial: Fluids vs No fluids for Contrast Nephropathy prevention: A visualabstract

An animated #visualabstract for the recent AMACING study published in Lancet 2017 that was a randomized controlled trial for prevention of CIN with IV fluids vs placebo.

Below is a non animated version of the abstract

Monday, March 6, 2017

Nephmadness 2017: A Historical Perspective

NephMadness 2017 full logo

Every March, the nephrology social media scene is taken over by the one and the only- Nephmadness, an homage to the annual US college basketball tournament fondly known as March Madness. 

In early 2013, while I led the AJKD blog as editor, Joel Topf and Matt Sparks came up to me and said " Let's do March Madness version of Nephrology",  Being surrounded mostly by Cricket and soccer( the real football) most of my childhood and life, March Madness was something I learnt from my nephrology buddies. The idea was totally amazing!  What was even more amazing was that the AJKD editorial team took the risk with us on embarking on this venture.  And then it was born- March 2013- the first ever Nephmadness competition( the modern version of Nephrology Uptodate).  A collection of ideas, concepts competing year after year. 

I would recommend all to read prior years competitions- It's like reading a nephrology textbook but with fun and flavor and attitude-- totally cool! You can also read last year’s helpful guide, NephMadness for Dummies, for more details.

Prior years winners were

An editorial in AJKD highlighted this event in 2015. This is an example of reverse blogging leading to publication. Usually publications lead to blog posts and twitter events. The Nephmadness phenomenon lead to an invited editorial in the home journal describing the big event in Nephrology. The link is below

This year the tournament has 32 nephrology concepts divided across 8 different topic areas, called regions. Each region has 4 concepts. We have selected content experts from each topic to help us determine the best concepts and vet the information we provide to make sure it is accurate, unbiased, and interesting. The topics are secret until the contest begins on March 7, 2017- this year. Visit the AJKDBlog to get more information in 2 days.  

From 2013, to now, we have come a long way. More participants, more faculty, more involvement. This might have become the largest Medical online Game in history-- probably! I don't know of anything like this. If you do, let me know. If you don't, let the World records holders be ware!

Come play and enjoy! and most important of all- learn.
Students, fellows, residents, attendings, fellowship programs, all can participate.
Check out @kidneyCathy from Australia doing a "what is nephmadness" for all of us. 

Follow the NephMadness Team (listed below) to get engaged!

Tuesday, February 28, 2017

Perspective: Double Standards in Medicine

Image result for phone conversationIn a cold march morning in 2021 a big city urban “academic” hospital, the “consult” phone rings. A Nephrology attending answers “ Renal consult, can I help you?”.  The “Hospitalist” on the other end says, “ Yes, I have a creatinine of 1.5mg/dl, AKI, please see.”.  The Nephrologist replies, “ Yes, we shall, please send me details of the location and will take care of it.”  The Hospitalist says, “ thank you, and please don’t ask you fellow to see, I want an “Attending only” consult.  The Nephrology attending politely agrees.  He nods to the “renal fellow” next to him and says, “ Don’t worry, this one is for me only”. The Hospitalist continues “One more thing, I am done for the day, it’s 4PM, can you call the consult recommendations to my resident in house, thanks!” and hangs up.

Not too long ago, we trained as residents and fellows to see patients and get the “ nuts and bolts” of medicine and the field you were choosing. You wanted to see more patients to get the experience; perhaps not all of us but most of us wanted to get the “full and complete “ experience.  Attendings saw patients with us and we learnt from their clinical wisdom. While fellows/residents were work horses, most academic centers had educational missions as well to counterbalance the workload. Things have changed in the last decade. The above conversation reflects some of those changes.

What is wrong with the above conversation? What has bought us to this stage or might get us to this stage? Why is it “okay” for the “team” calling the consult to have trainees see their patients and “consult” team has to be “attending only”?  While a fellow might have less experience, their vision is not tunneled and they might bring an amazing differential diagnosis to the forefront.  While the fellow might be seeing many patients, seeing more patients might make them more efficient and learn to prioritize. There is lot of learning even when the volume of patients is high.  Is it the fear of “patient satisfaction” or is it a fear of “litigation”?  Not really sure.  I have heard it’s “communication” and many subspecialty fellows “don’t want to see more patients.”  Is that really true? Maybe once in a while, we all get tired and want to “go home”.  But we most of us went into medicine to “see patients” and provide optimal patient care.  I can say proudly that sometimes my patients ask “ Where is the fellow?, you are alone today? We miss the fellow..”  You form a team and a “team” always brings more to patient care than a “single person”. 

In addition, “consult” team cannot ask any questions. “ Yes sir, I shall see the patient”. Questions are asked to see the urgency of situation, to assess workup and to get a sense of what can be done quickly before we get there. “Asking questions on the phone” does not equate “avoiding” a consult. A good consultant will ask pertinent 1-2 questions and see the patient.  “Fellows” ask too many questions.. perhaps they are avoiding the consult.  Fellows ask questions to learn about the patient- it’s simple. Most fellows are nervous and want to make sure that when they present to their “attending”, they have a complete story.  Unfortunately, this is sometimes mistaken as “ avoiding consults”.  How quickly many attendings forget—“ I was once a trainee and did the same!”.
In the era of corporate medicine, where “academia” is blending with “private practice”, there is soon going to be no difference.  “Pan-consultemia” will drive these consults that will increase medical costs even more.   “Attending only” services are good to help off load the fellows burden in many academic centers and creating such services is an excellent idea for that reason.  When a surgical team calls a “attending only renal consult” and I don’t even get to speak to an “attending” on the other end-let alone a fellow or resident- it boggles my mind.

Double standards in medicine!

Friday, February 24, 2017

ASN Online Journal Chat on onconephrology topic

Dear Onco-Nephrology and Transplant Community members,

On Monday, February 27 at 9:00 pm EDT the Onco-Nephrology community is hosting a journal chat on immune checkpoint inhibitors and all ASN members are invited!

Here is how you can participate: 
  1. Join the Onco-Nephrology Community, if you haven't already
  2. Set your community notification settings for the Onco-Nephrology Community only to “Real Time”
  3. Read the Topic Summary on line or listed below.
  4. Watch your inbox on Monday for the discussion to start and participate in the chat
If you have any questions about setting up your notifications, please contact ASN Communities Associate Zach Cahill

Summary of topic by Mona Doshi, MD

The goal of any course of cancer treatment is to prevent and/or kill future growth of malignant cells. Sometimes this can be challenging as some cancer cells gain the ability to “trick” the immune system into thinking the cancer cells are normal healthy cells. Doctors are seeing promise in a group of drugs called immune checkpoint inhibitors, which actually “open up the immune system” and allow the immune system(T-cells) to recognize and attack the cancer. Two recent reviews published in early 2017 have summarized the effects of immune check point inhibitors (ICI) on the kidney.
We shall be discussing NEJM letter published on Jan 12th 2017. While effective in most cancer patients, this course of treatment has been less successful in kidney transplant patients because activating the immune system causes the patient’s body to start rejecting their donor kidney.  Five prior cases published in the literature of renal transplant patients getting PD-1 inhibitors have resulted in rejection. The rejections were mostly seen in PD-1 inhibitor based therapy compared to CTLA-4 therapy. In addition, the 2 cases of liver transplant where these agents were used and 1 case of heart transplant didn’t lead to a rejection episode.  But in the renal transplant patients, 5 cases have now been reported of leading to acute cellular and antibody mediated rejection when PD-1 inhibitor was administered. In a recent case correspondence in NEJM Jan 12th 2017 issue, the authors observed during the treatment of a patient living with cancer who had a kidney transplant that the combination of steroids and sirolimus (an immunosuppressant that has anti cancer properties),  could prevent a patient’s body from rejecting the organ during  cancer treatment with ICI.
In the case the authors observed the treatment of a 70 year-old Caucasian male who received a kidney transplant in 2010 and recently underwent treatment for small bowel cancer which had spread to the liver. The patient was given prednisone, a steroid, and sirolimus prior to incorporating an immune checkpoint inhibitor (nivolumab). The steroids were started 1 week prior to the starting of nivolumab and continued at a tapered regimen as mentioned in the manuscript to prevent the immune mediated reaction seen in prior cases. Steroids didn’t hinder the shrinkage of the cancer. There was significant response in tumor burden (as shown in the appendix) and the serum creatinine remained stable (as shown in appendix). There were no clinical or immunological signs of rejection.
In this forum discussion, as nephrologists, we can try to come up with ways to answer few questions for the oncologists.
1. What is the best treatment strategy for ICI induced AIN (dose, duration of steroids)?
2. What is the best preventive strategy for patients who have had ICI induced AIN and need to continue the targeted therapy?
3. Given the above single case report, can the above mTOR inhibitor+ steroid strategy be employed in all transplant patients receiving PD-1 inhibitors?

If you have questions about the content of the chat, contact any of the ONC leaders.

The Onco-Nephrology Leadership Team

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